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Degruyter Chem Chem-2021-0032 347..357 ++ Open Chemistry 2021; 19: 347–357 Research Article Belgin Sever, Mehlika Dilek Altıntop*, Yeliz Demir, Cüneyt Türkeş, Kaan Özbaş, Gülşen Akalın Çiftçi, Şükrü Beydemir*, Ahmet Özdemir A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity https://doi.org/10.1515/chem-2021-0032 received December 2, 2020; accepted February 9, 2021 1 Introduction Abstract: In an effort to identify potent aldose reductase Type 2 diabetes (T2D) is a chronic life-threatening disease (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), characterized by abnormally high blood glucose levels which were prepared by the solvent-free reaction of 2,4- resulting from impaired response of target tissues to thiazolidinedione with aromatic aldehydes in the presence insulin (insulin resistance) and/or progressively reduced in vitro of urea, were examined for their AR inhibitory function of pancreatic β cells. The global burden of T2D is -( - - - - activities and cytotoxicity. 5 2 Hydroxy 3 methylbenzyli increasing considerably, and therefore there is an urgent ) - - (3) dene thiazolidine 2,4 dione was the most potent AR need to develop safe and potent antidiabetic agents [1–5]. inhibitor in this series, exerting uncompetitive inhibition Polyol pathway is a two-step metabolic pathway K ± with a i value of 0.445 0.013 µM. The IC50 value of in which glucose is reduced to sorbitol, which is then 3 fi - compound for L929 mouse broblast cells was deter converted to fructose. The abnormally activated polyol mined as 8.9 ± 0.66 µM, pointing out its safety as an AR pathway has been reported to participate in the patho- inhibitor. Molecular docking studies suggested that com- genesis of T2D complications [5–11]. pound 3 exhibited good affinity to the binding site of AR Aldose reductase (AR) catalyzes the NADPH-depen- (PDB ID: 4JIR). Based upon in silico absorption, distribu- dent reduction of glucose to sorbitol as the first and rate- tion, metabolism, and excretion data, the compound is limiting enzyme of the polyol pathway. Under euglycemic predicted to have favorable pharmacokinetic features. conditions, the reduction of glucose is a minor function Taking into account the in silico and in vitro data, com- of AR owing to the relatively low affinity (high K ) of AR pound 3 stands out as a potential orally bioavailable AR m for this substrate. However, under hyperglycemic condi- inhibitor for the management of diabetic complications as tions, excess intracellular glucose leads to an increase in well as nondiabetic diseases. the enzymatic conversion of glucose to sorbitol, NADPH- Keywords: aldose reductase, thiazolidinedione, cytotoxi- consuming reaction in tissues possessing insulin-inde- city, molecular docking pendent glucose transport. Sorbitol does not diffuse readily through cell membranes due to its strong hydro- philic feature and accumulates in cells causing osmotic stress and cellular damage, particularly in lenses. Further- * Corresponding author: Mehlika Dilek Altıntop, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, more, the concurrent NADPH deprivation impairs the 26470 Eskişehir, Turkey, e-mail: [email protected] activity of other NADPH-dependent enzymes and causes * Corresponding author: Şükrü Beydemir, Department of an imbalance between the generation of intracellular Biochemistry, Faculty of Pharmacy, Anadolu University, 26470 reactive oxygen species and cellular antioxidant defense. ş Ş Eski ehir, Turkey; The Rectorate of Bilecik eyh Edebali University, Concomitantly, pseudohypoxia, which results from the 11230 Bilecik, Turkey, e-mail: [email protected] + - Belgin Sever, Kaan Özbaş, Ahmet Özdemir: Department of NAD depletion during the oxidation of sorbitol to fruc Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, tose by sorbitol dehydrogenase, causes further metabolic 26470 Eskişehir, Turkey and signaling alterations by exacerbating redox imbal- Yeliz Demir: Department of Pharmacy Services, Nihat Delibalta Göle ance. Fructose, the end product of the polyol pathway, Vocational High School, Ardahan University, 75700 Ardahan, Turkey is more reactive than glucose as a glycating agent; and Cüneyt Türkeş: Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24100 Erzincan, Turkey the increased formation of fructose also gives rise to Gülşen Akalın Çiftçi: Department of Biochemistry, Faculty of pathological conditions by promoting protein glycation Pharmacy, Anadolu University, 26470 Eskişehir, Turkey and the formation of advanced glycation end products Open Access. © 2021 Belgin Sever et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. 348 Belgin Sever et al. and thus leading to alterations in protein functions. Apart were also carried out to estimate their physicochemical from its role in T2D complications, AR is an important parameters for the evaluation of their oral bioavailability mediator in oxidative and inflammatory-signaling path- and drug likeness. ways implicated in the pathophysiology of cardiovas- cular disorders, sepsis, and cancer. In this context, AR is identified as a multidisease target for the design of potent agents able to counteract the development of 2 Experimental section long-term T2D complications as well as nondiabetic dis- [ – ] eases 5 13 . 2.1 Chemistry The recent findings related to the pathophysiological role of AR have led to the discovery of a great variety of AR inhibitors so far, and most of them have been evalu- 2.1.1 General ated in preclinical and clinical trials. However, their development is mostly hampered by low in vivo potency, 2,4-TZD and urea were procured from Acros Organics adverse effects, or pharmacokinetic drawbacks [5–13]. (Geel, Belgium) and VWR Chemicals (Leuven, Belgium), 2,4-Thiazolidinedione (TZD) stands out as a privi- respectively. Aromatic aldehydes were purchased from leged scaffold for the identification of promising thera- Alfa Aesar (Karlsruhe, Germany) or Sigma-Aldrich (St. peutic agents for the management of T2D, targeting a Louis, MO, USA). Melting points (MPs) were detected plethora of crucial enzymes/receptors such as peroxi- using Electrothermal IA9200 MP apparatus (Staffordshire, some proliferator-activated receptor gamma, AR, protein UK). Infrared (IR), nuclear magnetic resonance (NMR; tyrosine phosphatase 1B, and so on [14–26]. In the search 1Hand13C), mass spectra, and elemental analyses for novel AR inhibitors, 2,4-TZDs are of great importance were recorded on IRPrestige-21 FT-IR spectrophotometer as safer bioisosteres of hydantoin, which is considered (Shimadzu, Tokyo, Japan), Varian 400 MHz FT-NMR spec- as the main cause of hypersensitivity reactions provoked trometer (Agilent, Palo Alto, CA, USA), VG Quattro Mass by some AR inhibitors, such as sorbinil. Currently, only spectrometer (Agilent, Minnesota, USA), and Perkin Elmer epalrestat (EPR) bearing a 2-thioxo-4-thiazolidinone EAL 240 elemental analyzer (Perkin-Elmer, Norwalk, CT, scaffold (Figure 1) is commercially available in few Asian USA),respectively. countries (such as Japan and India) as an AR inhibitor approved for the management of diabetic neuropathy. This agent is able to slow the progression of diabetic 2.1.2 Synthesis of 5-(arylidene)thiazolidine-2,4- neuropathy and ameliorate its symptoms without any diones (1–8) serious side effects after long-term use. However, further long-term comparative studies should be carried out to A mixture of aromatic aldehyde (2 mmol) and 2,4-TZD elucidate its efficacy in different patient populations [5]. (2 mmol) in the presence of urea (20 mmol) was heated Taking into account the knowledge obtained so far in an oil bath at 150°C for 2 h. Upon completion of the [5–26] and the potential of TZD-based small molecules as reaction, it was then dispersed with hot water and col- AR inhibitors [14–26], herein we reported the preparation lected by filtration. The product was crystallized from of new 2,4-TZDs and in vitro studies related to their AR ethanol [27]. inhibitory activities and cytotoxicity toward L929 mouse fibroblast cell line. In an effort to explore their possible binding modes in the binding site of AR, molecular docking studies were performed. In silico absorption, dis- 2.1.2.1 5-(2-Fluoro-4-methoxybenzylidene)thiazolidine- tribution, metabolism, and excretion (ADME) studies 2,4-dione (1) Yield: 88%. MP: 215–220°C. −1 IR νmax (cm ): 3450.65, 3367.71, 3080.32, 3007.02, S S 2843.07, 1728.22, 1708.93, 1668.43, 1616.35, 1593.20, O N O 1573.91, 1506.41, 1436.97, 1388.75, 1342.46, 1313.52, OH 1294.24, 1269.16, 1251.80, 1190.08, 1161.15, 1093.64, 1028.06, 950.91, 871.82, 858.32, 825.53, 806.25, 756.10, Figure 1: Epalrestat. 729.09, 713.66, 692.44, and 646.15. 2,4-Thiazolidinediones as potent AR inhibitors 349 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 3.80 (s, 3H), 2.1.2.4 5-(2-Hydroxy-5-methoxy-3-nitrobenzylidene) 6.38 (s, 1H), 6.86–6.89 (m, 1H), 7.68 (d, J = 9.6 Hz, 1H), thiazolidine-2,4-dione (4) ( ) ( ) 8.49 s, 1H , 10.41, and 11.18 2s,1H . – 13 Yield: 74%. MP: 245 246°C. C NMR (100 MHz, DMSO-d6) δ (ppm): 55.76 (CH ), 3 IR ν (cm−1): 3562.52, 3425.58, 3334.92, 3076.46, 101.61 (d, J = 25.0 Hz, CH), 110.79 (CH), 113.05 (d, J = max 2945.30, 1693.50, 1681.93, 1668.43, 1598.99, 1537.27, 1531.48, 12.8 Hz, C), 116.12 (C), 127.85 (CH), 130.23 (d, J = 3.8 Hz, 1454.33, 1344.38, 1307.74, 1242.16, 1197.79, 1166.93, 1095.57, CH), 155.41 (C), 160.85 (d, J = 11.5 Hz, C), 165.23 (C), and ( ) 1041.56, 929.69, 837.11, 752.24, and 665.44. 167.44 C . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 3.81 (s, 3H), MS (FAB) m/z 254.11 [M + H]+. 6.72–6.88 (m, 1H), 7.87–8.02 (m, 1H), 8.47 (s, 1H), 10.26 Anal.
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